Insulin binding to monocytes and insulin sensitivity in anorexia nervosa

Insulin Binding to Monocytes and Insulin Sensitivity in Anorexia Nervosa

VIJAY R. SOMAN, M.D.* PHILIP FELIG, M.D.+ New Haven, Connecticut

From the Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut. This work was supported in part by grants (4M 21158, AM 13526 and RR 125) from the National Institutes of Health. Requests for reprints should be addressed to Dr. Vijay Soman, Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street. New Haven, Connecticut 06510. Manuscript accepted August 6,1979. * Recipient of a Clinical Investigator Award [AM 00356) from the National Institutes of Health. + Established Investigator of the American Diabetes Association.

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In six female patients with anorexia nervosa, we examined specific binding of 1251-insulinto monocytes and in vivo sensitivity to insulin before and after treatment. Insulin sensitivity was determined by the rate of glucose disappearance during an intravenous insulin tolerance test (KITT). In the untreated state, the patients with anorexia nervosa were 26 to 41 per cent below ideal weight and amenorrheic. Fasting plasma glucose and insulin levels were, respectively, 20 per cent and 55 per cent below those observed in healthy controls. Insulin binding to monocytes was 70 per cent gr,eater than that in controls. Scatchard analysis of the insulin binding data revealed an increase in binding capacity with no change in binding affinity. During the insulin tolerance test, Kn-r (9.7 f 0.7 per cent*min-I) was 50 per cent greater in untreated patients than in healthy controls. Following treatment with behavior modification, there was a gain in body weight to within 2 to 11 per cent of ideal body weight, and menstrual function returned. Plasma glucose and insulin levels rose to values similar to those in healthy controls. Insulin binding declined by 40 per cent to values comparable to those in the controls. The decrease in insulin binding was due to a reduction in binding capacity. The plasma glucose response to the insulin tolerance test (Kn-r) fell 50 per cent below pretreatment values to levels comparable to those in healthy controls. Both before and after treatment, an inverse correlation was observed between plasma insulin concentration and insulin binding to monocytes whereas a direct correlation was demonstrable between insulin binding to monocytes and Ku-r. The data indicate that in anorexia nervosa insulin binding to monocytes and in vivo sensitivity to insulin are increased. The increase in insulin binding may be a consequence of a decrease in plasma insulin and may, in turn, be responsible for the increase in insulin sensitivity. The increases in insulin binding and insulin sensitivity return to normal following regain of body weight. Anorexia nervosa is characterized by a starvation-like state. Previous studies from our laboratory indicate that in obese subjects complete starvation results in a discussion between insulin binding and insulin sensitivity as reflected by increased insulin binding to monocytes but decreased insulin action [l]. Similar findings have been reported in starved animals [2]. Recently Wachslicht-Rodbard et al. [3] reported that insulin binding to erythrocytes is increased in patients with anorexia nervosa. In the present study we examined the relation between insulin binding to monocytes and in vivo insulin sensitivity in patients with anorexia nervosa. Our findings demonstrate that anorexia nervosa is characterized by increased insulin binding to monocytes which correlates directly with augmented sensitivity to insulin-induced hypoglycemia and which is reversed by refeeding.

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Clinical Data and Plasma Glucose, Plasma Insulin, 1251-tnrulinBinding to Monocytes and Insulin Sensitivity (Krrr) in Patients wlth Anorexia Nervosa Before and After Treatment and in Normal Controls

TABLE I

Duration

01lllneu

Patient

Age (yr)

1 2 3 4 5 6

17 24 16 20 18 19

4 2-$ 1 3 4 2

19.0 f1.2

2.8

Mean fSEM

(yr)

Amenorrhea Before Alter + + + + + +

l

MATERIALS

different different

AND

m

Plasma insulin (@JW Before After

Befo!:g’d’dl)mer 66 72 70 74 68 59 68’

f0.5

Normal controls (N=9) Mean 20.0 fSEM fl.O Significantly + Significantly

-

Plasma Glucose

% ideal

f2

98.0 f2.5

96 89 93 98 98 _--

72 72 65 82 80 75

95+ f2

74’

94 90 88 92 89 -__

5.0 6.0 4.0 10.0 7.5 5.3

91+ fl

f2

95.0 f4.0

6.3’ f0.9

14.4 f0.8

‘251-lnsulin Binding (%) Before Alter

K,,, (%* min-‘) Before After

12.5 14.0 11.9 14.5 -----

12.8 11.9 14.5 10.0 10.7 11.2

7.6 7.2 8.0 6.8 6.2

13.2+ f0.6

11.9’ so.7

7.2+ f0.3

7.0 so.3

11.0 8.6 12.0 7.2 9.0 10.1 9.7’ f0.7

5.2 6.0 6.6 4.8 5.0 --5.5+ f0.3

6.1 f0.5

from values in normal controls, p
METHODS

Subjects. Six female patients with anorexia nervosa of one to four years’ duration were studied in the untreated state (Table I). Five of the patients were restudied during remission following behavior modification therapy and regain of body weight. The diagnosis of anorexia nervosa was established according to the criteria of Feighner et al. [4]. At the time of study. none of the patients were taking any medication or had evidence of other associated disease. The average caloric intake of the patients during the anorectic phase of the disease was 980 f 100 kcal/day. During the four days prior to study. the carbohydrate intake of all patients was increased to at least 200 g/day with a total caloric intake of 1,300 f 92 kcal/day. During the four days prior to repeat studies performed during the remission phase, the total caloric intake of the patients was 2,500 f 210 kcal/day. The patients were compared to a group of normal volunteers consisting of nine age-matched (16 to 24 years] female subjects who were within IO per cent idcal body weight (Metropolitan Life Insurance Table, 1959). All subjects gave informed written consent prior to their voluntary participation in the study. Insulin Tolerance Test. All studies were carried out with the patients in the postahsorptive state (10 to 14 hour overnight fast). An indwelling catheter was inserted in an antecubital vein, and two hasal blood samples were drawn 15 minutes apart for the measurement of plasma glucose [5], insulin [6], cortisol [71and serum growth hormone levels [a]. An additional blood sample (-60 ml) was obtained for measurement of ‘““I-insulin binding to monocytes. Crystalline insulin (0.1 U/kg) was then administered intravenously, and additional blood samples were collected for the determination of plasma glucose (at 5 minute intervals), and serum growth hormone and plasma cortisol (15 minute intervals) levels. 1251-Insulin Binding Studies. 1’51-insulin binding to circulating monocytcs was determined as previously described [1,9]. Briefly, mononuclear cells obtained by Hypaque-Ficoll cen-

January

trifugation [lo] were incubated at a concentration of 2.5 to 5 X lo7 cells/ml with lz51-monoiodo insulin (0.2 ng/ml) with and without unlabeled porcine insulin in 0.5 ml of Hepes buffer (pH 8.0) for 180 minutes at 22“ C. The amount of bound lz51insulin was determined by the centrifugation method [l]. The per cent monocytes in the mononuclear cell preparation (quantitated by the nonspecific esterase method [ll]) was similar in control subjects (14.0 f 0.9 per cent) and in patients with anorexia nervosa before (13.5 f 1.1 per cent) and after treatment (13.0 f 1.8 per cent). The degradation of 1Z51-insulin under assay conditions was not significantly different in control subjects (6.0 i 0.9 per cent) as compared to patients before (8.0 f 0.6 per cent) and after treatment (6.0 f 0.6 per cent) (P >0.5). Nonspecific binding of lZ51-insulin to monocytes was similar in patients before (0.90 i 0.07 per cent of total radioactivity) and after treatment (0.76 f 0.11). and in controls (0.78 f 0.10). Other Endocrine Tests. In addition to determining the plasma cortisol and growth hormone response to the insulin tolerance test, all patients had a thyrotropin-releasing hormone [TRW) stimulation test (500 pg intravenous bolus) for determination of thyroid-stimulating hormone (TSH) reserve 1121.Basal blood samples were also obtain& for measurement of &rum thyroxine [13], estimated free thyroxine [13], serum prolactin 1141. serum luteinizing hormone (LH) [l5] and serum folliclcstimulating hormone (FSH) [16] before and after treatment. In addition, 24 hour urine was obtained for measurement of 17-ketosteroid (17-KS) [17] and 17-hydroxycorticoid (17-OCHS) excretion [18] in the untreated state and following trcatment. Data Analysis. The insulin binding data were analyzed by Scatchard analysis [19] to determine the total binding capacity. To evaluate tissue sensitivity to insulin, the plasma glucose response to the insulin tolerance test was analyzed in terms of the rate constant (KITT) for the decrease in plasma glucose (per cent decrease per minute], as calculated from the value for the half-time of glucose disappearance [20].

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L Figure 1. Competition curves of 1251-insulinbinding to monocytes in control subjects and in patients with anorexia nervose before and after treatment. Data are expressed per 1 X 10’ monocytes/ml and corrected for nonspecific binding. The shaded area indicates mean control values f 1 SEM.

Statistical analyses were performed using the paired and unpaired t tests as appropriate, analysis [21].

and by linear

regression

RESULTS

As shown in Table I, all patients with anorexia nervosti had amenorrhea and were from 26 to 41 per cent below ideal body weight. In patients with untreated anorexia nervosa plasma glucose and plasma insulin levels were, respectively, 20 per cent and 55 per cent lower than those in age-matched controls. Specific binding of lz51-insulin to monocytes was 70 per cent higher than in controls (Table I]. As indicated in Figure 1, the increase in insulin binding was demonstrable at all concentrations of insulin indicating an increase in insulin-binding capacity, rather than a change in affinity. The latter conclusion is further supported by the observation that, in the untreated patients, the insulin concentration required for a 50 per cent decrease in specific binding of 1251-insulin (6.0 f 0.3 ng/ml) was similar to that in the controls IS.2 f 0.3) Scatchard analysis (Figure 2) of the insulin-binding data revealed parallel curvilinear plots in untreated patients and controls. The total insulin-binding capacity in the untreated patients (2.3 f 0.1 ng/ml/l X lo7 monocytes) was 80 per cent higher than in control subjects (1.25 f 0.05 ng/ml, P
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associated with an increase in plasma glucose and plasma insulin levels, whereas lz51-insulin binding fell significantly to the level of control subjects. The decrease in insulin binding was seen at all concentrations of insulin [Figure 1). The Scatchard plot shown in Figure 2 revealed that the total insulin-binding capacity (1.3 f 0.1 ng/ml) fell by 45 per cent to a level indistinguishable from that of controls. The insulin concentration required for a 50 per cent decrease in lZ51-insulin binding (6.4 f 0.3 ng/ml) was unaltered following treatment, remaining similar to control levels. The decrease in insulin binding after treatment was accompanied by a 50 per cent decrease in KIT, Figure 3 shows the relation between insulin binding to monocytes and the glucose response to the insulin tolerance test (KITT).As shown, a direct linear relation between insulin binding and Krm was observed in patients with anorexia nervosa both before (r = 0.88, p <0.005) and after treatment (r = 0.73, p <0.05). Figure 4 depicts the relation between insulin binding and plasma insulin levels in controls and patients with anorexia nervosa. In control subjects a significant inverse correlation was observed between insulin binding and plasma insulin levels (r = -0.95, p
1

INSULIN

BOUND

lng/ml)

_1

Flgure 2. Scatchard analysis of insulin binding to monocytes in control subjects and in patients with anorexia nervosa before and after treatment. The shaded area indicates mean control values f 1 SEM. The intercepts at the abscissa indicate the total insulin binding capacity for each group: A = patients with anorexia nervosa before treatment: B = patients with anorexia nervosa after treatment; C = control subjects.

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were all within normal, limits both before and after treatment. Serum prolactin levels were in the upper range of normal whereas serum LH and FSH levels were in the low normal range (p
I6 r

Anorexia n

Nsrvosa

Untreated

A Post-treatment

2 t 01

0

I

I

I

I

I

I

I

1

2

4

6

6

IO

12

14

16

K ITT Figure 3. Correlation between ‘zsI-insulin binding to monocytes and in viuo insulin sensitivity (Krrr. %/min-‘) in patients with anorexia nervosa before and after treatment. The correlation coefficient (r) for the combined group was 0.96 (p
IN ANOREXIA

NERVOSA-SOMAN.

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16 . 14 -

.

2

‘2

g

IO-

Control*

loorsrio

. . .

Nprvoro

.

“ntr.e+ed

.

Po*t-trsatm.“t

. .

0

z

l

m

z i : 7 d N

8-

. .:

.

.*. . 6

.* .

4

21

Figure 4. Correlation between fasting plasma insulin levels and 1251-insulinbinding to monocytes in control subjects and in patients with anorexia nervosa before and after treatment. The correlation coefficient (r) for all subjects combined (control and patients with anorexia nervosa) was -0.96 (p
gained menstrual function and demonstrated a reversal of endocrine abnormalities. The present findings demonstrate that anorexia nervosa is characterized by an increase in insulin binding to monocytes (Table I]. Following treatment, there was a fall in insulin binding to the level of control ‘* subjects. The increase in insulin binding in our patients was due to an 80 per cent higher insulin-binding capacity, whereas insulin receptor affinity, as reflected by the insulin concentration required for a 50 per cent decrease in insulin binding (Figure l), remained unaffected. These data are in agreement with the studies of Wachslicht-Rodbard et al. [3] demonstrating that in anorexia nervosa insulin binding is increased and is restored to normal with refeeding. Regarding the mechanism of the increase in insulin binding, we observed an inverse correlation between insulin binding and plasma insulin concentration in patients with anorexia nervosa in the untreated state as well as following treatment (Figure 4). Since insulin has been shown to regulate its own receptor concentration in in vitro [25] as well as in vivo studies [1,26,27], it is likely that changes in insulin binding in anorexia nervosa may be secondary to the alterations in ambient insulin concentration. It should, however, be noted that Wachslicht-Rodbard et al. [3] failed to observe a correlation between plasma insulin concentration and insulin binding in patients with anorexia nervosa. It should also be pointed out that an inverse correlation between insulin binding and insulin level, such as observed in the present study, is by no means universal to hypoinsulinemic states. For example, studies from our

January 1980 The American Journal of Medicine

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TABLE 1

Basal Hormone Levels Before and After Treatment In Patients wlth Anorexla Nervosa Urinary 17-KS (mgl24 hr) Before AHer

Patients 1 2 3 4 5 6

7.0 10.2 11.1 9.6 13.0 7.5

Mean fSEM

9.7 f0.9

Normal range

Urinary 17-GCHS (mgI24 hr) Before After

7.2 7.9 9.0 9.0 10.5 -

4.5 7.6 8.6 7.9 4.9 5.9

4.0 7.0 7.2 7.8 6.2 -

Serum Thyroxine Be,&:9

%) Alter

7.5 9.0 5.4 6.4 5.5 6.0

7.0 6.2 5.4 6.8 6.0 -

Estimated Free Thyroxine (ne %) Before After 1.4 1.7 1.2 1.4 1.3 1.6

5-15

Mean

3-10

4.6-9.2

1.0-2.1

19.5 30.5 22.0 18.0 19.0 -

3.0 1.0 1.5 5.2 2.5 1.0

<20

12.0 10.0 13.8 9.8 16.6 -

Serum FSH (mlU/ml) Before After 4.6 2.0 1.5 3.5 1.0 6.0

9.6 15.0 20.0 12.0 13.5 -

5-25

4-24

[23], employing the intravenous insulin tolerance test, indicate an increased insulin sensitivity in the majority of patients. However, in those studies the carbohydrate intake prior to the study was not standardized, and the effect of treatment on the response to the insulin tolerance test was not examined. The findings in the present investigation [in which all subjects received at least 200 g carbohydrate a day for four days prior to study] indicate that in the untreated state, anorexia nervosa is associated with a 50 per cent increase in insulin sensitivity as determined by the KITT. Furthermore, following treatment there is a normalization of the plasma glucose response to the insulin tolerance test. Moreover, a direct correlation was observed between insulin binding and insulin sensitivity both before and after treatment. To the extent that the monocyte is reflective of insulin binding in other tissues [32], the current findings support the conclusion that changes in insulin binding may be

Serum Growth Hormone (nglml) After Before Peak’ Basal Basal Peak’

18.4 15.6 20.4 18.0 24.0 12.0

5.0 3.5 6.0 8.5 5.2 3.2

18.0

30.0 32.6 40.9 39.0 36.0 22.0 33.4

fl.7

f2.8

12.6 15.0 12.5 17.5 21.0 -__ 15.7 fl.6

28.8 34.0 35.0 39.0 44.0 --36.2 f2.5

5.2 f0.8

15.0 12.4 24.0 18.0 20.4 38.9 21.3 f3.7

12 11.8 19.8 20.0 26.0 ___

1.0 3.5 1.0 4.6 1.5 2.0

10.0 12.6 14.0 12.0 18.0 15.6

2.1 1.0 1.2 2.4 1.6 -__

9.8 16.0 13.5 18.0 20.0 ___

2.2 f0.5

17.9 f2.7

2.3 f0.6

13.6 fl.1

1.7 f0.3

15.5 fl.8

O-5 basal >7peak

5-24basal 2-3X peak

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Serum TSH (pLUmI) Before After PeakT Basal Peakr Basal

3.2 1.0 1.2 1.6 3.8 ___

Indicatesmaximal levels achieved duringinsulintolerancetest. t Indicatesmaximal levels achieved duringTRH stimulation test.

70

20.0 16.0 31.4 16.0 12.0 19.0

Plasma Cortisol (pg %) After Before Peak’ Basal Peak’ Basal

fSEM Normal range

Serum LH (mKJ/ml) Before After

(@ml) Before Alter

Basal and Poststlmulation Hormone Levels in Patients with Anorexia Nervosa Before and After Treatment

TABLE III

1 2 3 4 5 6

1.1 1.6 1.1 1.6 1.4 -

Serum Prolactin

8.7 6.6 6.4 6.6 6.7 1.4 1.4 19.1 21.8 2.4 12.8 3.0 14.0 f0.6 60.7 f0.7 f0.6 f0.5 f0.08 f0.13 f2.7 f2.3 f0.6 fl.6 f0.8 il.7

laboratory have shown a lack of correlation between insulin binding and insulin levels in conditions such as isolated growth hormone deficiency [9] and following exercise [28]. Since the monocyte is not a conventional target site of insulin action [such as the liver, muscle and fat cell] and, thus, may not necessarily be reflective of changes in insulin binding and/or sensitivity in other tissues, in the current study we examined the plasma glucose response to intravenous insulin (Ktrr] and its relationship to insulin binding to monocytes. With respect to insulin sensitivity in anorexia nervosa, previous data are somewhat conflicting. In studies based on oral glucose tolerance tests, responses including a “flat curve” and a delayed decrease in plasma glucose have been observed and in some instances were interpreted as indicative of insulin resistance [29,30].On the other hand, the data of Landon et al. [31] and Mecklenberg et al.

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responsible, at least in part, for augmented ins& sensitivity in anorexia nervosa. It should be noted that the intravenous insulin tolerance test provides a less physiologic qtiantitation of tissue sensitivity to insulin than is achieved with other procedures such as the insulin clamp technique [l]. In addition to tissue sensitivity to insulin per se, the plasma glucose response to intravenous insulin may be influenced by the counterregulatory hormone reshonse evoked by hypoglycemia [%I. Nevertheless, the intravenous insulin tolerance test has been used to examine insulin sensitivity in obesity [34] and maturity onset diabetes [XJ]. Furthermore, the increased insulin sensitivity as reflected by the elevated KITT observed in untreated patients with anorexia nervosa in the present study is unlikely to be due to an inadequate counterregukitory hormone response to hypoglycemia. As shown in Table III, the plasma cortisol arid serum growth hormone responses to the insulin tolerance test were clearly in the normal range.

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It is of interest to compare the changes in insulin binding and sensitivity observed in anorexia nervosa with those repotted in prolonged starvation. In obese subjects fasted for three to lodays, there is an increase in insulin binding to monocytes which i_saccompanied by a decline in insulin sensitivity [I]. A similar dissociation between insulin binding and insulin action has been observed in fasted rats [z]. The findings in complete starvation thus contrast with the parallel changes in insulin binding and insulin sensitivity which characterize anorexia nervosa. The data thus suggest that the factors regulating insulin-mediated glucose metabolism in anorexia nervosa may differ from the regulatory mechanisms in starvation.

ACKNOWLEDGMENT We would like to thank Hana Cohen and Patricia Grantham for expert technical assistance.

REFERENCES DeFronzo RA. Soman V, Sherwin RS, et al.: Insulin binding to monocytes and insulin action in human obesity, starvation and refeeding. 1Clin Invest 62: 204.1978. Olcfsky JM: Effects of fasting on insulin binding, glucose transport, and glucose oxidation in isolated rat adipocytes: relationships between insulin receptors and insulin action. J Clin Invest 58: 1450,1976. Wachslicht-Rodbard H, Gross HA, Rodbard D, et al.: Increased insulin binding to eythrocytes in anorexia nervosa. Restoration to normal with refeeding. N Engl J Med 300: 882,1979. Fcighner JP, Robins E, Guze SB, et al.: Diagnostic criteria for use in psychiatric research. Arch Gen Psychiat 26: 57, 1972. 5. Huggett ASG, Nixon DA: Use of glucose oxidase, peroxidase and 0-dianisidinc in determination of blood and urinary glucose. Lancet 2: 368,1957. 6. Wise JK, Hendler R, Felig P: Influence of glucocorticoids on glucagon secretion and plasma amino acid concentrations in man. 1Clin Invest 52: 2774,1973. 7. DeMoor P, Steen0 0, Rankin M. et al.: Fluorimctric determination of free plasma ll-hydroxycorticosteroids in man. Acta Endocrinol (Copenh) 33: 297,196O. 8. Rosselin G, Assan R, Yalow RS, et al.: Separation of antibody-bound and unbound peptide hormones labelled with iodine-131 by talcum powder and precipitated silica. Nature 212: 355; 1966. 9. Soman V, Tamborlane W, DeFronzo R, et al.: Insulin binding and insulin sensitivity in isolated growth hormone deficiency. N Engl J Med 299: 1025,1978. IO. Boyum A: Separation of leukocytes from blood and bone marrow. J Clin Lab Invest 21 (suppl97): 77.1968. 11. Li Cy, Lam KW, Yam tT: Estcrases in human lcucocytes. j Histochem Cytochem 21: 1, 1973. 12. Ode11 W, William J, Paul WE: Radioimmunoassay of thyrotropin in human serum. J Clin Endocrinol Metab 25: 1179,

16.

17. 18. 19. 2n.

1962. ‘1.

22. 23. 24. “5.

26. 27.

1965.

13. Seligson H, Seligson D: Measurement of thyroxine by compcfitivc protein binding. Clin Chim Acta 38: 199, 1972. 14. Sinha YN. Sclby FW, Lewis OH. et al.: A homologous radioimmunoassay for human prolactin. J Clin Endocrinol Metab 36: 509.1973. 15. Schalch DS, Pilrlow AF, Boon RC, et al.: Measurement of

human leutelnizing hormone in plasma by radioimmunoassay. J Clin Invest 47: 665, 1968. Ode11 WD, Rayford PL. Ross GT: Simplified, partially automated method for radioimmunoassay of human thyroidstimulating, growth, luteinizing and follicle stimulating hormones. J Lab Clin Med 70: 973,1967. Bongiovanni AM, Eberlein WR, Thoman PZ: Use of an organic base in the Zimmerman reaction. J Endocrinol 17: 331,1957. Silber RM: Standard Methods of Clinical Chemistry, ~014. New York, Academic Press, 1963, p 113. Scatchard G: Attractioris of proteins far small molecules and ions. Ann NY Acad Sci 51: 660.19&?. Lundbaek K: Intravenous glucose tolerance as a tool in definition and diagnosis of diabetes mcllitus. Br Med J I: 1507,

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“9. 30,

January 1980

Snedecor GW. Cochran WG: Statistical Methods, 6th ed, Ames, Iowa, Iowa State University Press, p 593. Travaglini P. Beck-Peccoz P, Ferrari C, et al.: Some aspects of hypothalamic-pituitary function in patients with anorcxia nervosa. Actn Endocrinol (Copenh) 81: 252,1976, Mecklenburg RS, Loriaux DL. Thompson RM, et al.: Hypothalamic dysfunction in patients with anorexia nervosa. Medicine (Baltimore) 53: 147.1974. Aono T, Kinugasa. T, Yamamota T. et al.: Assessment of gonadotropin secretion in women with anorexia nervosa. Acta Endocrinol (Copenh) 81: 630,1975. Gavin JR III, Roth J, Ncville DM Jr, et al.: Insulin-dependent regulation of insulin receptor concentrations: a direct demonstration in cell culture. Proc Nat1 Acad Sci USA 71: 84, 1974. Kobayashi M, Olefsky JM: Effect of experimental hyperinsulinemia on insulin binding and glucose transport in isolated rat adipocytes. Am J Physiol235: E53. 1978. DeFronzo RA, Dcibcrt D, Hendlcr R, et al.: Insulin sensitivity and insulin binding to monocytes in maturity onset tiiabetes. J Clin Invest 63: 939, 1979. Soman VR, Kaivisto VA, Grantham P, et al.: Increased insulin binding to monocytes after acute exercise in normal man. J Clin Endocrinol Metab 47: 216, 1978. Bartels ED: Studies on hypometabolism. I. Anorexia ncrvosa. Acta Mcd Stand 124: 185, 1946 Kanis JA, Brown P, Fitzpatrick K, et al.: Anorexia nervosa:

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a clinical, psychiatric and laboratory study. Q J Med 43: 321. 1974. 31. Landon J, Greenwood FC, Stamp TBC, et al.: The plasma sugar, free fatty acid, cortisol and growth hormone rcsponse to insulin, and the comparison of this procedure with other tests of pituitary and adrenal function. II. In patients with hypothalamic or pituitary dysfunction or anorexia nervosa. J Clin Invest 45: 437,1966. 33. Olefsky JM: Decreased insulin binding to adipocytes and circulating monocytes from obese subjects. J Clin Invest 57: 1165,1976.

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33.

34.

35.

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Gather AJ, Cryer PE, Santiago JV, et al.: The role of adrencrgic mechanisms in the substrate and hormonal response to insulin-induced hyperglycemia in man. J Clin Invest 58: 7, 1976. Harrison LC, Martin FIR, Melick RA: Correlation between insulin receptor binding in isolated fat cells and insulin sensitivity in obese human subjects. J Clin Invest 58: 1435. 1976. Beck-Nielsen M: ‘The pathogenic role of an insulin-receptor defect in diabetes mellitis of the obese. Diabctcs 27: 1175,

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